The hepatitis G virus (HGV) is a newly discovered member of the flaviviridae family that has approximately 25 percent homology with hepatitis C virus (HCV). Its clinical significance is unknown. We have studied HGV and its relation to blood transfusion risk. HGV was found in approximately 1.5 percent of the donor population and was shown to be transfusion transmitted by the acute appearance of HGV RNA following transfusion, linkage between HGV positive donors and infected recipients, and a higher incidence in transfused subjects as compared with nontransfused controls. HGV was shown to persist in the majority of infected subjects, but almost 40 percent appear to clear the virus over time. Although 3 of 13 patients (23%) with non- A, non-B, non-C transfusion-associated hepatitis had acute HGV infection, the causal role of HGV in these case is not clear because there was no definite temporal relationship between the HGV RNA level and alanine aminotransferase (ALT) elevations and because one case had alternate explanations for the ALT abnormalities. Overall, of 35 observed and 84 projected HGV infections, only 4 percent occurred in patients with hepatitis (the three cases described above), 7 percent occurred in those with coexisting HCV where the ALT elevations were shown to be HCV related, 16 percent were in recipients who had such minor ALT elevations that they were not classified as having hepatitis, and 73 percent occurred in recipients with no biochemical or clinical evidence of hepatitis. Hence, the vast majority of HGV-infected patients have no evidence of liver disease and in the few who do, causality cannot be proved. Similarly, we have studied HGV in renal dialysis patients, patients with hemophilia, intravenous drug users, and patients with acute and chronic non-A, non-B, non-C, non-D, and non-E hepatitis. Although the prevalence of HGV is very high among parenterally exposed individuals (10-20%), there is no association with liver disease in these HGV-infected populations. Among HGV and HCV coinfected patients, it was shown that HGV did not worsen the course of the coexistent HCV infection.